Discovery of octahydropyrrolo [3,2‐b] pyridin derivative as a highly selective Type I inhibitor of FGFR3 over VEGFR2 by high‐throughput virtual screening

Wang, Xin; Ye, Cheng‐hao; Li, En‐min; Xu, Li‐Yan; Lin, Wang‐qiang; Chen, Guanghui

doi:10.1002/jcb.30357

Cited by 4 publications

(2 citation statements)

References 64 publications

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“…This is the reason why it presents fewer adverse reactions due to VEGFR2 inhibition (such as diarrhea, vomiting, and fatigue [ 212 ]). The evidence of its antitumor activity was demonstrated in several FGFR-expressing cell lines and in animal models with FGFR translocations or amplifications [ 212 , 213 ].…”

Section: Fgfr Inhibitorsmentioning

confidence: 99%

The Importance of the Pyrazole Scaffold in the Design of Protein Kinases Inhibitors as Targeted Anticancer Therapies

Nitulescu,

Stancov,

Seremet

et al. 2023

Molecules

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The altered activation or overexpression of protein kinases (PKs) is a major subject of research in oncology and their inhibition using small molecules, protein kinases inhibitors (PKI) is the best available option for the cure of cancer. The pyrazole ring is extensively employed in the field of medicinal chemistry and drug development strategies, playing a vital role as a fundamental framework in the structure of various PKIs. This scaffold holds major importance and is considered a privileged structure based on its synthetic accessibility, drug-like properties, and its versatile bioisosteric replacement function. It has proven to play a key role in many PKI, such as the inhibitors of Akt, Aurora kinases, MAPK, B-raf, JAK, Bcr-Abl, c-Met, PDGFR, FGFRT, and RET. Of the 74 small molecule PKI approved by the US FDA, 8 contain a pyrazole ring: Avapritinib, Asciminib, Crizotinib, Encorafenib, Erdafitinib, Pralsetinib, Pirtobrutinib, and Ruxolitinib. The focus of this review is on the importance of the unfused pyrazole ring within the clinically tested PKI and on the additional required elements of their chemical structures. Related important pyrazole fused scaffolds like indazole, pyrrolo[1,2-b]pyrazole, pyrazolo[4,3-b]pyridine, pyrazolo[1,5-a]pyrimidine, or pyrazolo[3,4-d]pyrimidine are beyond the subject of this work.

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Section: Fgfr Inhibitorsmentioning

confidence: 99%

The Importance of the Pyrazole Scaffold in the Design of Protein Kinases Inhibitors as Targeted Anticancer Therapies

Nitulescu,

Stancov,

Seremet

et al. 2023

Molecules

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show abstract

“…MD simulations of proteins can be used to investigate the ligand binding and enzyme reaction mechanisms. [42][43][44][45][46][47][48] To investigate the interactions between α-TOH and CYP4F2, we performed the MD simulations on wide type CYP4F2 (wt4F2) and mutants using the AMBER 16 software package. 49 The protonated state of CYP4F2 was determined through the online H++ server (http://biophysics.…”

Section: Simulationsmentioning

confidence: 99%

Insights into the binding mechanism between α‐TOH and CYP4F2: A homology modeling, molecular docking, and molecular dynamics simulation study

Liang

Zheng

2023

J of Cellular Biochemistry

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α‐Tocopherol (α‐TOH) is a potent antioxidant. The concentrations of α‐TOH in plasma are closely related to human health. α‐TOH can be regulated by the metabolism of cytochrome P450 4F2 (CYP4F2). However, the atomic‐level basis for this regulation process remains elusive. Here, we successfully constructed the structure of CYP4F2 by homology modeling and obtained the α‐TOH–CYP4F2 complex models using molecular docking. Three parallel 500 ns molecular dynamics simulations were performed on each complex model to investigate the details of the interaction between α‐TOH and CYP4F2. MM–GBSA method combined with principal component analysis shows that 8 key residues establish a hydrophobic cavity stabilizing α‐TOH in the pocket of CYP4F2 and S423 forms an important hydrogen bond with α‐TOH anchoring α‐TOH in the favorable position for ω‐hydroxylation. Based on our simulation results and the experimental facts, we designed mutation simulation experiments to clarify the important role of two key residues (S423 and V433) in the binding of α‐TOH with CYP4F2. The results show that the mutations directly or indirectly change the binding mode of α‐TOH and decrease its binding affinity with CYP4F2, which is unfavorable for ω‐hydroxylation. Our results could enrich the information on structure‐function relationships of CYP4F2 and provide valuable insights into the regulatory mechanism of CYP4F2 on the metabolism of α‐TOH.

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FGFR3 alterations in bladder cancer: Sensitivity and resistance to targeted therapies

Noeraparast,

Krajina,

Pichler

et al. 2024

Cancer Communications

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In this review, we revisit the pivotal role of fibroblast growth factor receptor 3 (FGFR3) in bladder cancer (BLCA), underscoring its prevalence in both non‐muscle‐invasive and muscle‐invasive forms of the disease. FGFR3 mutations in up to half of BLCAs play a well‐established role in tumorigenesis, shaping distinct tumor initiation patterns and impacting the tumor microenvironment (TME). Emphasizing the importance of considering epithelial‐mesenchymal transition profile and TME status, we revisit their relevance in predicting responses to immune checkpoint inhibitors in FGFR3‐mutated BLCAs. This writing highlights the initially promising yet transient efficacy of the FGFR inhibitor Erdafitinib on FGFR3‐mutated BLCA, stressing the pressing need to unravel resistance mechanisms and identify co‐targets for future combinatorial studies. A thorough analysis of recent preclinical and clinical evidence reveals resistance mechanisms, including secondary mutations, epigenetic alterations in pathway effectors, phenotypic heterogeneity, and population‐specific variations within FGFR3 mutational status. Lastly, we discuss the potential of combinatorial treatments and concepts like synthetic lethality for discovering more effective targeted therapies against FGFR3‐mutated BLCA.

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Discovery of octahydropyrrolo [3,2‐b] pyridin derivative as a highly selective Type I inhibitor of FGFR3 over VEGFR2 by high‐throughput virtual screening

Cited by 4 publications

References 64 publications

The Importance of the Pyrazole Scaffold in the Design of Protein Kinases Inhibitors as Targeted Anticancer Therapies

The Importance of the Pyrazole Scaffold in the Design of Protein Kinases Inhibitors as Targeted Anticancer Therapies

Insights into the binding mechanism between α‐TOH and CYP4F2: A homology modeling, molecular docking, and molecular dynamics simulation study

FGFR3 alterations in bladder cancer: Sensitivity and resistance to targeted therapies

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